DE1493987A1 - Dibenzocycloheptene derivatives and processes for their preparation - Google Patents

Description

DR.-1NG. WALTER ABITZ DR. DIETER MORF

Patent attorneys

8 Munich 27, Pienzenauerstraße 28 Telephone 483225 and 480415 Telegrams: Chemindus Munich

14S3S87 i *. Sep 1968

9174 / M 61 297

P 14 95 987. 8
New documents

MERCK & CO., INCORPORATED Rahway, New Jersey, V.St.

Dibenzocycioheptene derivatives and processes for their preparation

The present invention relates to dibenzocycioheptene derivatives, especially 11 "Hydroxy" 10, ll = dihydro "5" · (> = subst. "aminopropyl) -SilO ^ epoxy-SH-dibenzo ^, ^ cycloheptene * and a method for their production.

The invention relates to compounds of the general formula

^8AD

909830/13 ^ 6

■ ι

and their non-toxic acid addition salts »and a method for the preparation of these compounds »which is characterized in that one is a compound of the general formula

heated in an inert solvent in the presence of an acidic catalyst and optionally the compound obtained "in which R ^{w is} lower-alkyl, acylated in the 1!.,""position, the acylated compound is reacted with alkyl, aralkyl or aryl haloformate and the compound thus obtained is hydrolyzed.

In the formulas given above, R 'denotes a straight-chain or branched lower alkyl radical, preferably up to 6 carbon atoms; B "a straight-chain or branched lower alkyl radical» preferably with up to 6 carbon atoms or

-2- 909830/1366

BATH ORIGINAL

Hydrogen or R * and R * ¹ together are piperidyl-O), pyrrolidyl- (l), morpholinyl- (4) or l «lower-alkyl-piperazinyl- {4) and X and X ^f , which can be the same or different from one another , mean in each case a hydrogen atom, a halogen atom, an alkyl group with up to 6 carbon atoms, an alkenyl group with up to 6 carbon atoms, a trifluoromethyl group, a hydroxyl group, an alkoxy group with up to 4 carbon atoms, a mercapto group an aikylmeroapto group with up to 4 carbon atoms , an alkylsulfony! group with up to 4 carbon atoms, a sulfamoyl group, an alkylsulfamoy! group with up to 4 carbon atoms or a dialkylsulfamoy! group with up to 8 carbon atoms, There can be more than one of the substituents X or X * on each of the berizolden Rings be present. The 5-propyl side chain can have substituents, for example lower alkyl radicals, preferably with 1-4 carbon atoms.

Dft "invention ageml *" method is used by virtue of increased Temperature carried out. Preferred catalysts are p-toluenesulfonic acid. Fibrous acid, trifluoroacetic acid or hydrogen chloride.

A wide variety of solvents can be used, however a lower alkenol such as methanol, ethanol, isopropanol and the like is preferably used. If the product is insoluble in the solvent used, it can (as a salt)

" ³ " 909830/1368

BATH ORIGINAL

obtained by filtration and further according to the usual working methods getting cleaned. If the product is in the solvent used is soluble, ao it can (in the form of the base) by evaporation of the Solvent, diluting with water, neutralizing any residual acid with so much alkali that the medium becomes basic is made, and filtering off the precipitate formed can be recovered.

To prepare those compounds of the structural formula for which R "is restricted to hydrogen, the corresponding compound in which the radicals R ¹ and R" are both lower alkyl radicals and preferably identical radicals can be dealkylated by removing the 11 -hydroxy group Slotted acylation, reacted the aeylerte compound with a haloformic acid, alkyl, aralkyl or aryl ester and the resulting urethane compound of the general formula

COOR

(R ^v - alkyl, aralkyl or aryl) is hydrolyzed.

909330/1366

BATH ORIGINAL

The condensation of the tertiary amino compound with a Halogenfoxmlat to form the corresponding ürethanzwischenprodukts can in the absence of a solvent, but preferably _W can be performed in the presence of a solvent ird. Suitable solvents are e.g. B. aromatic hydrocarbons such as benzene and toluene «aliphatic hydrocarbons such as heptane and hexane, and the halogenated hydrocarbons such as chloroform and. Carbon tetrachloride. The reaction can be carried out at room temperature, but the use of elevated temperature is preferred. After completion of the reaction, the urethane is recovered after removal of basic material by evaporation of the solvent.

The urethane intermediate produced ao is then, preferably under basic conditions, hydrolyzed. After the Hydrolysis is the desired © product in a conventional manner, for example dOTSI ?. Extraction into a suitable solvent and evaporation of the solvent, obtained.

The in-acidic compounds available have anti-depressive activity. As antidepressants, they can be administered orally _s z. B. In the form of tablets, powders or granules with delayed F.fsisetzusig or orally or parenterally in the form of aqueous LüSsussgen or suspensions -be administered. Most Satisfied: * lentto results are obtained with a daily dosage of

BAD ORIGINAL .5. » 909830/1366

about 1 to about 2500 mg. Preferably the new funds in doses distributed over the day or in single dosage forms administered with sustained release. The connections will preferably used in the form of their non-toxic acid addition salts and the preparation of these salts is within the scope of this invention. .

It can be seen that the compounds obtainable according to the invention exist in geometric isomers. Your bacemate can according to usual working methods, such as fractional crystallization of the Salts with optically active acids are split into the enantiomorphs. The two isomers have pharmacological activity, however, the effectiveness of one isomer can be considerably greater than that of the other isomer.

It should be noted that if the carbinols used as the starting material contain a nuclear substituent, the transfer in the 5, lQ-epoxy-II = hydroxy derivative one of two compounds JIe according to the direction of the ring closure, surrender-karm. becomes a 6-member If carbinol is used, the product can be in the 3- or 7-position substituted 5,10-epoxy-11-hydroxy <derivative, and it will be designated 5 (7) in the following examples, if applicable used.

909830/1366

BATH ORIGINAL

example 1

cie-10,11 -Dlhydro-5- (3-dlmethylamlnopropyl) -5 »10-epoxy · 11-hydroxy-SH-dlbenzo / a, d7oyolohepten

A solution of 2.95 β (0.008 NoX) ole-3arl2a-Dlnydro-2,2-methyl-8-C-dimethylaminopropyl) -8-hydroxy-δΗ-ΰΙοβηιεο - ^, *: 6.27oyolohepta / T, 2-dj7la; 5-dioxole and 3.0 g (0.0158 mol) p-toluenesulfoneHure-mono hydrate in 300 al of absolute methanol for 4 hours RUokfluse

heated. The solution is mixed with 16 ml of 1 m potassium hydroxide in methanol neutralized «and the solvent is then distilled off under reduced pressure. The residue is partitioned between benzene and water and the aqueous layer is re-extracted twice with benzene, the combined benzene extracts are washed with water, dried by filtering through paper and then evaporated to dryness under reduced pressure. By crystallization of the residual from Festpubstanz 50 £ ethanol the product is obtained from the F - 145-152 ⁰ C in a yield of 1.9 g (81%). An analytically pure sample melts at 151-153 ° C after repeated recirculation

sations made of cyclchexane. H 7 , 70 N 4 .53 analysis C _2Ä , N0 ₂ 7th 4th , 52 Calculated : C 77.64 Found: 77 # ό?

_Λ 909830/1360

OfilGINAL

917 *

, 1483987 8

01 · Production of the oie-ja, 12ß-Dlhydra-2,2-di "ethyl" 8-CJ-dimethylaelnopropyl) -e-hydroxy-eü-dibenio, used as the starting material

was as follows:

3-taBettaylaMinopropylBÄgneeiueohlorid is made from 290 mg (0.012 OraoBttoai) NagneslumspXnen and 1.7 g (0.012 mol) 2-dimethyl-. aminopropylohlorid in 12 al trook «no Tetrahydrofuran according to the 'procedure of US Pat. No. 3,066,283. Under a nitrogen atmosphere, a solution of 1.7 g (0.006 mol) of cis-3a, 12Q-dihydro-2,2-dimethyl-8H-dibenzo _< ^, 4: 6 _# l7cyolo-ηβρίβφδ - ^ - Ι, ^ - αΑοχοΙ -δ-τη in 13 ml of dry tetrahydrofuran was added dropwise to a solution of the Grignard reagent with cooling in an ice bath and with stirring. The dark yellow solution is allowed to come to room temperature and is stirred for 2 hours. Most of the solvent is then distilled off at room temperature under ver.Tlncertesn pressure. The residue is dissolved in 25 ml of benzene and 6 ml of water are added dropwise with stirring and cooling. The benzene mixture is decanted from the gelatinous lower ear which is then extracted three times with 50 ml of boiling benzene each time. The combined bensol extracts are washed repeatedly with water. The benzene vdrd evaporated and the remaining plague substance crystallized from 95% ethanol. This gives cis-> a-12ß-dihydro-2,2-dimethyl-8- (3-dimethyl- • Ainopropyl) -e-hydroxy-eH-dibenzo ^ J, 4: 6.27 <Jyoloh «Pta ^ r, 2-d7-1.3-dioxole in the form of white needles from P - 181-168 ° C in a pile ·

- ⁸ - 909830/13 **

BATH ORIGINAL

of 1.56 g (70 %) . Obs pure "product ouch another experiment melts at 189-190 ⁰ C after recrystallization from ethanol and 95Jfigem ouch isopropyl alcohol.

Analysis

Rebuilt: C. 75 » 17th H 7th , 95 N 4th .81 Found: 75 12th 7th , 82 , 01 BeIeDi • 1 2 •

c ie-10,11-Dihydro-5-O-dlmethylaminopropyl) -.5,10-epoxy-11-hydroxy bySd7lht

A solution of "^ 15" β (0.001 mol) ice-? A, 12Q-dihydro-8- (3-dimethyl-aninopropyl)>8-hydroxy-2-phenyl-8H'-dlbenzo> _i ^ i «d7cyelohepta / r, 2-> id (7 '1,3-dloxol and 58Ο mg (0.002 NoI). p-Toluolaulfonsftre-monchydrat in 40 ml of absolute methanol. is heated to reflux for 8 hours The cooled solution is bit 5 ml lm- Kalumhydroxyd made in methanol, and the solvent is distilled off under reduced pressure. The RUoketand is distributed between benzene and water, and after re-extraction of the aqueous phase with benzene, the combined benzene extracts are washed with water and dried by filtering with anhydrous sodium sulfate. Evaporation of benzene under reduced pressure left an oily residue is solidified by trituration with Ither and 200 substance (65%) from the .P - Sine delivers 137-144 ⁰ C · purified Prob with respect to the melting point (149-152 ⁰ C). , the Misohsohmels-

ORIGINAL BATHROOM "9- 909830/136 *

9174

Point and infrared response with the cis-lOill-Dihydro-S-Cj-dimethylaminopropylJ-SilO-epoxy-11-hydroxy-SH-dibenzo- ^ idToyclohepten produced according to Example 1 identical.

The preparation of the cis-3ot, 128-dihydro-8- (3-dimethylaminopropyl) -e-hydroxy-S used as starting material

was as follows:

} Following the procedure of Example 1, but using an equimolar amount of cisOuilSß-DihydroS-phenyl-eH-dibenzo _i / a, d7cycXohepta _< ^ r, 2-d [7-l, 3-dioxol-8ron instead of cis- 3a. »12ß-dihydro-2,2-dimethy) .- 8H-dibenzo- _wl ^ 3,4: 6,27 <3yä! Ohepta / T, 2 _{-d7-1 3} 3-dioxol-8-one is obtained cis-3a, 12β-bihydro-8- (3-diinethylaminopropyl

in the form of a white crystalline solid substance P = VCSN 155-161 C in a yield of 71, I- obtained by repeated Uinkrlstallismiiorier from 95Jiigem Athnnol reacting a sample analysemieine forward F "166-167 ⁰ C.

analysis

Calculated: C 78.04 H 7.04 N 3.37 %

Found: 78.09 7.21 3.42 %

- 10 -

909830/1366

BATH ORIGINAL

Beliplil 3

trans-10,11 "dihydro- 5- (3-diaethylantinopropyl) -5,10-epoxy- 11-hydroxy>5H-dlb" nzo / a. d7cyclohepten

Bin ventilation of 29, * β (0.08 mol) tran «-> a, 12e-dihydro-2,2-diB« thyl-

/ T, 2-d7-l, 3-dioxole and 30.5 g (0.16 hol) of p-tbluenesulfonic acid monophydrate in 2.3 l of absolute methanol are heated under RUokflu for 4 hours. The cooled solution is neutralized in 150 ml of 1 m potassium hydroxide in methanol, and the solvent is then distilled off under reduced pressure. The residue is partitioned between benzene and 5 % aqueous sodium hydroxide and water, and the aqueous layer is back-extracted three times with iron sol. The combined benzene extracts are washed with water, dried by filtering through anhydrous sodium sulfate and evaporated to turner under reduced pressure. By crystallisation of the remaining Festsubetanz from a mixture of benzene and cyclohexane erhHlt the white ;; se crystalline product from the F ■ I56-I60 ⁰ C in -this yield of 18 g (73%), ras pure product melts at I57-I58 ⁰ C after recrystallization from benzene and sublimation at 140 ^° C. and 0.01 mm.

Analysis ^C 20 ^H 23 ^N0 2

Calculated: C 77.64 H 7 # 49 N 4.53 % ; found: 77.73 7.71 4.73 %

" ""909830/136"

BATH ORIGINAL

The production of the trans-3a, 12Q-dihydro-2, 2-dimethyl-8- (3-dlmethylaminopropyl) -e-hydroxy-eH-dibenzo-

was as follows:

2-Dimethylaminopropyl magnesium chloride is prepared from 4.05 g (0.166 gram atom) of Magneaiumspltnen and 20.2 g (0.166 mol) of 3-dimethylaminopropylohlorld in 150 ml of dry tetrahydrofuran according to the method of OS Patent 3,046,28? manufactured. Under a nitrogen atmosphere, a solution of 23.2β (0.082 mol) trans-3a, 12Q-dihydro-2,2-dl ~ nethyl-eH-dibenzq ^^ sefj ^ oycloheptft ^ T ^ -dJ-lfS-dioxol-e-one in 100 ml of dry tetrahydrofuran was added dropwise to the solution of the Orignard reagent with cooling in an ice bath and stirring. The mixture is allowed to come to room temperature and is stirred for two hours. The majority of the 'solvent is then distilled off below 50 ° O under reduced pressure. The residue is dissolved in 150 ml of Bonzol and 20 ml of water are added dropwise with stirring and cooling. The benzene layer. is decanted from the gelatinous precipitate, which is then extracted four times with 100 ml of boiling benzene each time. The combined benzene extracts are washed with water and extracted three times with 100 ml each of 0.5m citric acid. The acidic extract is made basic with sodium hydroxide and the oily base which has separated out is extracted into benzene. After washing the combined extracts with water and drying over anhydrous sodium sulfate, the benzene is evaporated and the product is obtained in the form of a viscous yellow oil in a yield of 29.5 6 (96 %) .

" ¹² " 909830/136 «

BATH ORIGINAL

91 Γ- ¹

The base can be converted into the hydrogen oxalate by treating an ethereal solution with a solution of oxalic acid (10 % excess) in isopropyl alcohol. The acidic oxalate of trans-5a, 12B-dihydro-2, 2-dimethyl-8- (3-dimethylayninopropyl) -8-hydroxyeH-dibenzo ^ i ^^ ilToyolohepta / TjS-dZ-10-dioxole is in the form of a white crystalline Solid substance obtained from F * 169-172 ⁰ C (decomp.). Repeated itacrystallizations from mixtures of isopropyl alcohol and absolute star give the product from F »

173 ° C (dec.). ,

Analysis ^C 25 ^H 29 ^N0 3 * ^C 2 ^H 2 ° 4
Calculated: C 65.62 H 6.8?
Found: 65.08 6.72,

B e 1 s ρ l e 1 4

r-ll-acetoxy-10,11 -dihydro-5- (3-dimethylaminopropyl) -5, 1 0-ep.ojqr-5H 'dibenso / a, d7cy <3lohepten

A solution of 630 rag (0.00204 mol) cis-10, ll-dihydro-5- (3-dlniethyXaminopropsrl) -5,10-spoxy-l 1 -h3> droxy-5H-diben2c ^ i, d [7cyclchepte! ni in 12 mJ. Essip.diiureanhydri.dv / ird 4 l / S hours under RUökfluns ER- hit z%. The dark yellow I-solution! is evaporated to dryness under reduced pressure, and the oily residue is dissolved in 20 ml of water with a content of 100 ml of 6N salt. After a ßxtrak TiCN having £ snsoi the aqueous solution is made alkaline with sodium hydroxide and extracting the oily base in benzene. The washed ne benzene extract is evaporated under reduced pressure, whereby

the product a) .s oily residue to U
Trap weighs 600 ms (84 t).

BATHROOM ORIGINAL - 13 -.

The base may be (F 10. Ubtfsechuas) by treating a solution in laopropylalkohol with a solution of oxalic acid in isopropyl alcohol are converted into the Hydrogenoxaiat. The hydrogen oxalate of ois- · 1l-ethoxy-10,11-dihydro-5-t3-dimethyiaminopropyl), 5,10-epoxy-5H-dibenzoj / a, d7cycXohepten is in the form of a white crystalline powder substance from F »171-173 ⁰ C (2ers.) Received. Repeated recrystallization from isopropyl alcohol and from mixtures of absolute ethanol and absolute ether gives the product of P «175-175 ° C <decomp.). Analysis C ₂₂ H ₂₅ NO ₅ . C ₂ H ₃ O ^

Calculated: C 65.29 H 6.16 N 5.17 %

Found: 65.27 '6.40 p

Example 5

oie-ll-Acetoxj-Sy ^ -carbiithoxy-H-iHethylaininoJ-propyi.y-lO, 11 -di hd5105Kdlb / \ d / lht ""

Sine I <5suns of 600 ng (0.00172 Hol) cls-ll-acetoxy-lO.ll-dlhydro- 5- (3-diine thylaniinopropyl) -5, lO-epoxy-SH-dibenzo ^ / a ", d7cyclohepten in > ral troo5 * ersm benzene is added drop by drop to a solution of 0.7 ml of EthylefoXoa'formate in 2 ml of dry benzene with stirring. This removes a yellow hinge which, however, dissolves when the Gerriisch is warmed up the mixture is cooled under reflux, diluted with benzene and washed with ^ hydrochloric acid and then with water. Evaporation of the benzene under reduced pressure gives the product in the form of an oily residue , which typically weighs 650 msec (92.5 #)

909830/1366

¹⁴ ORIGINAL BATHROOM

Example 6

ois-io, 11-dihydro-StlO-epoxy-l1-hydroxy-5-O-methylamino propyl) -5H-dlbenzo> a _J d? cyclohepten '

A solution of 650 mg (0.00159 mol) of the crude urethane obtained in Example 5 and 500 mg (0.0089 mol) of potassium hydroxide in 10 ml of n->. Sutyl alcohol is stirred in a nitrogen atmosphere for 7 hours! heated under RUokfluss. The solvent is evaporated under reduced pressure and the residue is partitioned between benzene and water. After "ei extractions of the aqueous phase, the combined benzene extracts are ^mi water * washed and then extracted with 15 ml and with 10 ml of 0.5M citric acid. The benzene layer is then washed with water. Evaporation of the solvent under reduced pressure leaves the neutral material, cis-5-Ü-iN-Carb-; Methoxy-N-methylamirio) propyl | -10, ll-dihydro-5 »10, epoxy-11-hydroxy-5H-dibenzo ^> d_7cyelohepten, in the form of an oily residue, which typically weighs 150 mg. The citric acid extract is made alkaline with sodium hydroxide and the oily base is extracted into benzene. The washed® benzene extract is evaporated to dryness under reduced pressure.

The Umkristallisauicn of the residue from absolute yields Sther mg 128-150 ⁰ C in a yield of 110, the · product in the form of a by-step Icristalllnen solid of F ".

BATH ORIGINAL. :

* " ^i? ". 909830/1366

A solution of the Neufcralsn material and 250 mg (0.0045 mol.) Of potassium hydroxide in 4 ml of n-butyl alcohol is refluxed for 10 hours with stirring in a nitrogen atmosphere. The reaction mixture is worked up as described above, and the basic material crystallizes out absolute ether to give a further product from F «126-128 ⁰ C is obtained in a yield of 70 mg. The combined products (180 mg, 35 $) can be purified by ther Ümkristallisation from absolute ^ and sublimation at reduced pressure to give an analytically pure sample of F "Ijj8-1] 59 ⁰ C.

Analysis ⁰ IQ ¹⁵ SiN ¹ V

Calculated: C 77.85 H 7.17 N 4.74 % Found «77.07 6.95 4.91 %

Ex iel 7_

trans-11-Aeetoxy-lO, 1 l-dihydro-5- (3-dimethyXaminopropyI) - 5-t IQ epo xy ^ H-dibenao / aadiTgyclo hepten

By replacing the ois-10, n-.dihydro-5- (3-dlmefchylaminopropyl) -

by using an equimolar amount of the trans isomer and practically the same method as described in Example 4, trans-11-acetoxy-10,11-dihydro-5- (2-dimethylaminoprapyl) - '5 * is obtained 10 ~ epoxy-5H ~ dibenzo2 £, d7cyelohepten. The yield of the white crystalline base of F · 116.5 to 120 ⁰ C amounts to 79 Jg An analyzer ·. -

■ "·" ^Ιβ ' 909830 / 13sfe

ORIGINAL BATHROOM

At

pure sample melts at 125-126 ° C after TJracrystallization Petroleum ether *

Analysis ^C 22 ^ 25 ^N ^ 3

Calculated! C 75.18 H 7.17 N 3.99 # Found: 74.93 7.04 3.94 #

BAD original 909830/1366

Example 8

trans-11 -Acetoxy-S - /! * - (N-carbllthoxy-N-methylamino) -propyiy-

5 »5 g (0.0157 mol) trans-II-acetoxy-10, li-dihydro-5- (3-dimethylaminopropyl) -5,10-epoxy-5H-dibenzo ^, d7oyelohepten become 150 in small portions with stirring ml of ethyl chloroformate cooled in an ice bath was added. The mixture is stirred in the cold for 1 1/2 hours and then heated under reflux for 16 hours, excess chloroformate is distilled off under reduced pressure, the oily residue is treated with benzene and the mixture is evaporated to dryness under reduced pressure. This treatment is repeated and the residue is partitioned between benzene and water. The Benaolsohiöht is washed with water, 0.5 ^ · ° citric acid and water, dried by filtering through anhydrous sodium sulfate and evaporated to dryness under reduced Brniek. The crystallization of the oily residue from ether-petroleum ether gives the product from Ρ »75-76 ⁰ C in a yield of 2.4 g. A second fraction of 2 seconds of substance at a temperature of 72-73 ° C is obtained from the Muttei-taug ©. A cleaned sample melts at 77-78 ⁰ C after Usikrlstaliisierung from a mixture of absolute ^ ether and petroleum ether.

Analysis ^G 2 * i®27 ^ ®5

Calculated; C 70.40 H 6.65 %

Found: 69.78 6.8p %

- 18 - 909830 / 13.8 "6

BATH ORIGINAL

example 9

j- O-raethylamino-

traii910, lDihydro5,10epoxyn
propyl) -5H-dlbtnEo / ir.d7oyoloheDten

A solution of 4.1 g (0.01 mol) of trane-II-acetoxy-5-Z5 - (* - c. * Rbätbcxy-M-eethylamlno) -propy ^ -io, Π -dlhydro-5,10-epoxy -5H-dibenzo / a ^ oyclohepten and 20 g (0.558.MoI) potassium hydroxide in 100 al. n-Butyl alcohol is refluxed for 11 hours while stirring in a nitrogen atmosphere. The solvent is evaporated under pressure and the residue is partitioned between benzene and water. After two re-extracts of the aqueous phase, the combined bensol extracts are washed with water and then extracted three times with 100 ml of 0.5 oι lemons each time. The citric acid extract is made alkaline with sodium hydroxide and the oily base is extracted in benzene. The washed benzene extract is dried by filtering through anhydrous sodium sulfate and evaporated to dryness under reduced pressure. By crystallization of the oily residue from a mixture of absolute ether and petroleum ether. the product is obtained in the form of a white crystalline pest substance from P «! 28-129 ⁰ C in a yield of 1 * 5 g (31 $). One arrßlysenreine sample melts at 129-130 ⁰ C after sublimation at 115 ° C and 0.1 mm. Analysis C ₁₀ H ₂

Calculated: C 77.25 - H7 , 17th N 4.74 • *
Foundί 77.33 BAD ORiGlNAt 7th , 20 4.94 19th - 909830/1

Example 10

trans-10,11-Dihydrc-5-O-dimethylaminopropyl) -5.10-epoxy- 11 -hexano yioxy -SH-dibertzo / ä, d ^ syolohepten

A solution of 510 mg (0.001 mol) of trans-10,11-dihydro-5 - (^ - dimethylaminopropyl) -5,10-epoxy-II-hydroxy-5H-dibenzo ^ a, d7cyolohepten in 2 ml heated on a steam bath for 18 hours. The solution is stirred with 75 ml of water for 4 hours, then cooled in an ice bath and made strongly basic with aqueous sodium hydroxide. The oil base is extracted into benzene and isolated by evaporating the washed and dried benzene extract under reduced pressure. The remaining oil is dissolved in absolute ether and treated with an excess of maleic acid in absolute ethanol. The crystalline hydrogen maleate from P - 108-110. ⁰ C is obtained in a yield of 350 mg (67 %) . Recrietallizations from ethanol-ether and leopropyl alcohol-ether provide an analytically pure sample of P * 109-110 ⁰ C.

analysis C. eh 3 ^N0 3 . C ₄ ^H 4 ^G 4 12th N 2 , 68 * Calculated: 68 .81 H 7, 07 2 .62 Found: 68 , 61 7,

- 20 -

BATH ORIGINAL

Bel a ρ 1 e 1 ti

tran8-ll-aoetoxy-10, ll-dlhydro-5- (3-methylarainopropyl) - ^ iO5Hdlb / d7lht

A solution of 1.0 g (0.002 * 3 NoI) of trans-lOjll-dihydro ^ lO-epoxy-ll-hydroxy-5- (5-n »thylaBiiiopropyl) -5H-dlbentq ^ a, d7cyoloheptea-hydrogenioaleinate in 5» 1 Tiseseig and 5 ml 6N SalsaKure are stirred in an egg-salt bath while cooling. 50 ml of acetyl chloride are added drop by drop. Oma Rohren is continued for 1 hour in the cold and the solution is then reduced to below 25 ° under different pressure to a volume of 15 to 20 al. Diluting the remaining Löeung effected with 50 ml absolute ether, the precipitation of the hydrochlorides of the products P from "247 mg in a yield 850-249 ⁰ C (dec.). Repeated Umkristallieatlonen from absolute ethanol yield a product P - 254-255 ⁰ C (dec.).

analysis C. 67, i ^N0 5 . HCl 6th M. N 5.75 Calculated: 67, 47 H 6th »79 5.90 Found t FO

8AD ORIGINAL

9098 30 /

B e 1 s ρ I ₁ e, 1, 18

trans-11 -Benzoylaxy-10, 11 -dihydro-5- (3 = iaim <2thylainino ~ propyl) -

/ i7

618 mg (0.002 mol) trans-10, ll-dihydro = 5 ^ 3 ~ dimethylarainopropyl) -5,10-epoxy ~ ll-hydroxy-5H-dibenzo ^ _a d7-oyelohepten and 3 ml dry pyridine are cooled in an ice bath touched. 100 mg (0.0022 mol) of benizoylochloride are added dropwise. Stirring is continued in the cold for 1 hour, and the mixture is then left to stand for 2k hours at room temperature. After 45 minutes of heating on a steam bath, the mixture is poured into 50 ml of water. This reading is cooled in an ice fead and made strongly alkaline and the oily base which separates out is extracted into benzene. After washing the combined extract © with water, the benzene is evaporated, the product as. dissolved oil remains in a yield of 800 mg. The base is converted into the ε (yd? Oohlorld by dissolving it in 5 πΛ absolute thasiol and adding 0.35 ml 5 ₃ 92N ethanolic hydrogen chloride. Dilute with 25 ml absolute ether until crystallization begins causes the precipitate of trane-U-benzoyloxy-1 C, 11 - »aihydro-S- (3-diinethylaniinopropyl) -5 # 10-epoxy-5H =, dibenzo ^ fä ^ -ieyalohepten-hydroehlorltl from F 253-253 ° 0 (Zerso) mg in a yield of 790 llmkristallisationen from Isopropylaükohoi .and from abs;. (. Zero) iutem Älkohol-absolute ether raise the melting point to 259 * 5 © is 260.5 ⁰ C ·

Analysis ^S 27 ^H 27 ^M0 3 ' ^W1

Calculated: C 72, Οδ H 6.27 H?, U ji Found: 71.86 6.64 2.89 %

909830/1366 - £ 2. '.,....' BATH

917 *

149398? 13th

Example 13

tear- (-) -10,11 -dihydro-5- (3-dimethylaminopropyl} -5 # 10 »epoxy» llhdSHbdylh

12.36 g (0.0 * l · mol) racemisohes trans-10, H-dihydro-5- (3 «dimethyl · arainopropyl) -5» 10-epoxy-l 1 -hydroxy-SH-dibenEo ^. ^ Cyclohepten are dissolved in 200 ml of boiling absolute ethanol and treated with a solution of 6.0 g (0.04 KoX) of (-J-Weine & ure in 150 ml of warm absolute ethanol. Des (-) - tartrate crystallizes when the solution cools, and several yields are collected until no further precipitation occurs. The ethanolic mother liquor is then evaporated to dryness under reduced pressure and the remaining syrup is dissolved in 100 ml of water. The solution is made strongly alkaline with aqueous sodium hydroxide and the oily base is extracted in benzene . evaporation of the washed and dried benzene extract under reduced pressure gives the crystalline (-) -. base which weighs 1.52 g recrystallization from benzene-hexane gives 1.35 g of product from P, "15 ^ -157 ⁰ C.

The (-) - 3ase is dissolved in 20 ml of boiling absolute ethanol and treated with a solution of 655 mg (0.04.57 mol) of (+) - tartaric acid in 10 ml of warm absolute ethanol. The (+) - tartrate separates in white crystals from the 257-259 ⁰ G (decomp.) In a yield of 1.40. Recrystallization three times from 95% ethanol gives a product with a constant specific rotation of

_must

-27 ¹ ° ± 5 ° from P- 238 to 239 ⁰ C (dec.).

_BA D ofttcÄ · ί ^: ^ * 3 - 909830Π 36S

analysis

Calculated: G 68.58 H 6.82 % Found: 68.44 6.95 %

700 mg (0.00182 mol) of the (+) - tartrate are dissolved in 20 ml of water, The solution is made strongly basic with 5% aqueous sodium hydroxide and the oily base is extracted into benzene. Evaporation of the washed and dried benzene extract under reduced

.. '* Pressure gives the crystalline (-) - base. Recrystallize from a Garrison τοη benzene and hexane gives 476 mg of product from P «156 to

-158 ° Cma £ j & _Rmi - ' ⁿ ° ° C ± 5 to 10 *).

' ⁴ - Analysis C ₂

: Calculated C 77 * 64 ti f, 49 M 4.55 % . *

; Found «77.65 7 * 39 4.63 %.

Example 14

t rane - (+ ) -10,11 -Dihydro-5- (3-dimethylaminopr opyl) -5 > 10 .- epoxy-1-hydroxy-5H-dibenzoym ..dTeyclohepten -

■ -ml "* *

1.2, 36 g (0.04 mol) of racemic trans-10, 11 -dihydro-5- (3-dimethyl-, aminopropyl) -5 * 10-epo y-II-hydroxy-SH-dibenzo / ajdTcycloheptene will dissolved in 200 ml of boiling absolute ethanol and treated with a solution of 6.0 g (0.04 mol) of (f) -tartaric acid in 150 ml of warm absolute Ethanol treated. After adding 50 ml of 95% ethanol crystalline

the (+) - Tartrafc when the solution cools down and after several

Collected for rsn days at room temperature. The Ethiopian mother

, - 64 - 909830/1366

BATH ORIGINAL

Laug © is then evaporated to dryness under reduced pressure and the syrup that remains is dissolved in 100 ml of water. The solution is made strongly alkaline with aqueous sodium hydroxide and the oily base is extracted into benzene. Evaporation of the washed and dried Benssolextraktes under reduced pressure gives the crystalline (+) - base in a weight von.1,9 g P · 155-157 ⁰ C.

The base is dissolved in 20 ml of boiling, 95 # strength ethanol and mixed with

Solution of 925 mg (0 * 00615 mol) of (-) - tartaric acid in 5 ml of warm n ethanol. The (~) -tartrate precipitates in white crystals from F »238-259 ⁰ C (dec.). In a yield of 0.85 g from. A second crop of 0.75 S from the temperature 58-229 ° C. (decomp.) Is obtained from the mother liquor and combined with the first crop. Recrystallization three times from 95% ethanol gives a product

, " ^E + 290 ° + 5 °

with ei & er constant specific rotation £% ° J ^ a _n , " ^e + 290 ° + 5

P «S38 to 239 ⁰ C (dec.).

C 63.53 H δ, 82 % Found: 68.53 '6.71 %

950 mg (0.00247 mol) of dos (-) - tartrate are dissolved in 20 ml of water, and "the solution is made strongly basic with Seigern v / aqueous sodium hydroxide ima al® oily base extracted in benzene. Evaporation of the washed and dried ßenzene extract under reduced pressure gives the crystalline <<4 -) - ease. Recrystallization from a mixture of Bd & rwl and Eex & n gives 556 mg of product with a P »156 ble 158 ° C, ψ " ^ψ1100 ° (± 5 to 10 ^).

-85- 9098 30/13 left

BAD IGINAL

analysis ^C 2O ^H 22 ^N0 Calculated: C 77.64 Found: 77.71

H 7, ^ 9 H * # 52 #

7, ^ 2 4,6} j «

²⁶ "909830/1366

BATH ORIGINAL

Claims (1)

Heroic Bs Co. * 1493987 t ♦ · Sep. JSS8 987 * / M 61 ■ äAüt α it. “AMfoio. Hf * U V or R * and ¹ K ⁹ together J; or di-low- and their äiöhfct 2.018-10.11-134 ainopropyl) -5 * 10-epoxy- -η- ι, Mz New incidents Abs .: t *. f Sit Q830 / 1 -J- (3-aiethyiamiiio- 5. trans-10,11 -OlhydiO-5,10-epoxy-II-hydroxy-5- (3-methylaniino- 6. trans - (-) - 10, il-dihydro-5- (5 »dimethylaminopropyl) -5.10. epoxy-ll-hydroxy-SH-dibenzo ^^ d / cyclohept en. trans - (+) - 10,11-dihydro-5- (3-dimethylaminopropyl) - ■■ 'ίί ■■ If ir. Method for making the connections nAöfe Anepinioh 1 _# characterized in that Bah «ine connection of the more general. formula BATH ORIGINAL ti (R ¹ , R ", X and X ¹ have the meanings given in the claim; R" ^f and R ^wlf - hydrogen, alkyl, aralkyl or aryl) are heated in an inert solvent in the presence of an acidic catalyst and, if appropriate, the compound obtained , in which R "denotes lower-alkyl, acylated in the 11-position, the acylated compound with haloformic acid alkyl, aralkyl or · .- ■■. ¹ * γ * -aryl ester and hydrolyzed the compound thus obtained. r < 9. The method according to claim 8 »characterized in that ease one on increased temperature. 10. The method according to claim 8 or 9, characterized in that the acidic catalyst used is p-toluenesulfonic acid, sulfuric acid, Trifluoroacetic acid or hydrogen chloride is used. H. Medicines act off, characterized in that it is e | Ln * ^: compound according to claim 1. 909830/1366